Cefotiam hydrochloride is a semi-synthetic second-generation cephalosporin and its chemical name is (6R,7R)-7-[[(2-amino-4-thiazolyl)acetyl]amino]-3-[[1-[2-(dimethylamino)ethyl]-1H-tetrazol-5-yl]thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid dihydrochloride. There are many synonyms, for example, cefotiam dihydrochloride, hydrochloride cefotiam, Halospor, Pansporin, Pansporine, Spizef, Sporidyn, Cefapicol, Kemisporin, and Sepidnarin, and the like. Its molecular formula is C18H25C12N9O4S3, molecular weight: 598.55, CAS No.: 66309-69-1, a boiling point of 940° C. at 760 mmHg, and flash point: 522.3° C. On an anhydrous basis, the content of cefotiam shall not be less than 79.0%. The structure is as follows:

Regarding pharmacological toxicology of cefotiam hydrochloride, it is generally believed that its effect on Gram-positive bacteria is similar to that of cefazolin, and its effect on Gram-negative bacteria such as Haemophilus, Enterobacter, Escherichia coli, Craywhite coli and Bacillus mirabilis is excellent. It also has an antibacterial effect on Enterobacter, Citrobacter, and indole-positive Proteus. Its mechanism is binding to the penicillin binding proteins (PBPs) on the bacterial cell membrane to acylate transpeptidase, inhibits the synthesis of the septum and cell wall in the bacteria, affects the cross connection of mucopeptide components in the cell wall, and inhibits cell division and growth to make the bacterial morphology long, thereby finally dissolved and dying.
Clinically, cefotiam hydrochloride is mainly used for treating infections caused by sensitive strains, such as pneumonia, bronchitis, biliary tract infections, peritonitis, and urinary tract infections, as well as infections and sepsis after surgery or caused by trauma.
Many domestic and foreign patents and journals have reported the preparation method and purification method of cefotiam hydrochloride.
A method for preparing cefotiam hydrochloride is disclosed by Shanghai Ningrui Biochemical Technology Co., Ltd., which comprising the steps of: (1) introducing dry hydrogen chloride gas after adding the ATA material to a solvent, and then adding a chlorinating agent at a temperature of 0-30° C., and filtering ATC.HCL crystals after the reaction is complete; (2) dissolving 7-ACMT with a base in an aqueous solvent, adding ATC.HCL for acylation reaction at a temperature of −10-35° C., separating the organic solvent after the reaction is over, adding hydrochloric acid to the aqueous phase, adding a hydrophilic solvent whose volume is 3-6 times that of the aqueous layer, and precipitating cefotiam hydrochloride crystals. However, the yield of cefotiam hydrochloride prepared by the method is not high, and solvents such as dichloroethane, acetonitrile, and dimethyl formamide are used during the preparation process, where the residual solvent harms the human body.
The Chinese Patent CN 101633666 B reports a method for synthesizing cefotiam hydrochloride, comprising reacting 2-aminothiazol-4-acetic acid with formic acid to generate 2-formyl-aminothiazol-4-acetic acid, further adding 7-ACMT and triethyl amine, using N,N-diisopropyl-ethylamine and dimethyl formamide as solvents, and p-toluenesulfonyl chloride as a catalyst, stirring the reaction mixture, and then adding hydrochloric acid to obtain the target product. The cefotiam hydrochloride prepared by this method does not have a high purity, and has the problems of poor solvent residues and inconvenient post-treatment and use.
The Chinese patent CN 101544662 discloses a method of preparing a high purity cefotiam hydrochloride by crystallizing cefotiam or its crude salt product. Although this method can improve the purity of cefotiam hydrochloride, it is difficult to separate the inherent purities from the crude drug simply by dissolving, acid adjustment and base adjustment. Moreover, the process of adjusting pH will also bring new negative ion impurities, which increases the difficulty of separation.
Currently, various domestic manufacturers mainly rely on imported crude drugs to obtain cefotiam hydrochloride via dispensing. There are also manufacturers in China preparing such products, but both the yield and purity of the products are low. Accordingly, improving the purity of cefotiam hydrochloride is a problem anxiously to be solved, and has significant social and economic benefits.